Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([CH:39]([OH:48])[C:40]2[N:41]3[CH:47]=[N:46][CH:45]=[C:42]3[S:43][CH:44]=2)[CH2:37][C@H:36]([S:49][C:50]2[C@H:51]([CH3:74])[C@@H:52]3[C@@H:62]([C@H:63]([O:65][Si](C(C)(C)C)(C)C)[CH3:64])[C:61](=[O:73])[N:53]3[C:54]=2[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[CH2:35]1)=[O:33])[CH:29]=[CH2:30]>C1COCC1.C(OCC)(=O)C>[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([CH:39]([OH:48])[C:40]2[N:41]3[CH:47]=[N:46][CH:45]=[C:42]3[S:43][CH:44]=2)[CH2:37][C@H:36]([S:49][C:50]2[C@H:51]([CH3:74])[C@@H:52]3[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:73])[N:53]3[C:54]=2[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[CH2:35]1)=[O:33])[CH:29]=[CH2:30]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3csc4cncn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3csc4cncn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 38 h
Yield: 66.8 %

Procedure:
Acetic acid (0.26 ml) and 1.52 ml of a 1 M tetra-n-butyl ammonium fluoride/THF solution are added to a solution of 213 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidin-3-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate (stereoisomer B) in 4.5 ml of anhydrous THF, and the mixture is stirred in an argon atmosphere at room temperature for 38 hr. The reaction solution is diluted with 80 ml of ethyl acetate, the diluted solution is successively washed with 40 ml of a 1/15 M phosphate buffer (pH 7.0) and 20 ml of saturated saline, the washed solution is dried over anhydrous magnesium sulfate and filtered, and the solvent is removed by evaporation to give 193 mg of a slightly yellow oil. This oil is successively purified by column chromatography on silica gel (ethyl acetate:methanol=95:5→9:1) and on Sephadex LH-20 (chloroform:methanol=1:1) to give 119.2 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (stereoisomer B) as a milky white amorphous material.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([O:20][CH3:21])[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[NH:19])[NH2:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][C:35]=1[N+:44]([O-:46])=[O:45]>ClCCl>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([O:20][CH3:21])[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[NH:18])[NH:19][S:40]([C:37]3[CH:38]=[CH:39][C:34]([F:33])=[C:35]([N+:44]([O-:46])=[O:45])[CH:36]=3)(=[O:41])=[O:42])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: COC1(Cc2ccccc2F)CCN(c2ccc(C(=N)N)cc2)CC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1(Cc2ccccc2F)CCN(c2ccc(C(=N)NS(=O)(=O)c3ccc(F)c([N+](=O)[O-])c3)cc2)CC1
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 1H (0.200 g, 0.587 mmol) in dichloromethane (5 mL) was treated with triethylamine (0.245 mL, 1.76 mmol) and 4-fluoro-3-nitrobenzenesulfonyl chloride (prepared according to the procedure described in U.S. patent applicaiton Ser. No. 09/957,256, 0.169 g, 0.704 mmol), stirred overnight, and concentrated. The residue was purified by silica gel chromatography eluting with 40% ethyl acetate in hexanes to provide the desired product. MS (ESI) m/e 543 (M+H)+.
Reaction SMILES: C1N=CN([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])C=1.NC1C=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[OH:23]>CN(C=O)C>[N+:20]([C:18]1[CH:17]=[CH:16][C:15]2[O:23][C:6](=[O:7])[NH:8][C:9]=2[CH:10]=1)([O-:22])=[O:21]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2o1
Reaction time: 0.5 h
Yield: 434.9 %

Procedure:
CDI (1.57 g, 19.4 mmol) was added at 0° C. to a stirred solution of 2-amino-4-nitro-phenol (500 mg, 0.6 mmol) in DMF (5 mL) and the resultant was stirred for 30 mins. The mixture was poured onto ice and stirred for 10 minutes. The resulting precipitate was isolated by filtration to afford 470 mg (80%) of 5-nitro-3H-benzooxazol-2-one. 1H NMR: (DMSO-d6): δ 12.4 (b s, 1H), 8.05 (dd, 1H), 7.85 (d, 1H), 7.54 (d, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:18](O)[CH2:19][OH:20]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][CH2:9][C:10]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:20][CH2:19][CH2:18][O:11]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: OCCO
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)OCC1(c2ccccc2)OCCO1
Yield: 58.4 %

Procedure:
2-(tert-Butyldimethylsilanyloxy)-1-phenylethanone (8.0 g, 32 mmol), ethylene glycol (1.99 g, 32 mmol), and p-toluenesulfonic acid (50 mg) was suspended in benzene (50 ml). The mixture was stirred under reflux for 5 hours. The solvent was evaporated under reduced pressure. The residue was treated with water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The crude was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/1) to give tert-butyldimethyl-(2-phenyl-[1,3]dioxolan-2-yl-methoxy)silane (5.5 g, 18.7 mmol, 58%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1.[NH2:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:38]C(OC(C)(C)C)=O)[C:35]([OH:37])=[O:36])=[CH:29][CH:28]=2)[CH:24]=[C:23](Cl)[N:22]=1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[NH2:38][C@@H:34]([CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([O:13][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[N:14]3[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]3)[C:9]([F:12])([F:11])[F:10])[N:22]=[C:21]([NH2:20])[N:26]=2)=[CH:28][CH:29]=1)[C:35]([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Reactant: Cc1ccn(-c2cc(Cl)ccc2C(O)C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1ccn(-c2cc(Cl)ccc2C(Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
1-[4-Chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethanol (0.120 g, 0.41 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (0.176 g, 0.45 mmol), 1,4-dioxane (4 ml), and Cs2CO3 (0.533 g, 1.64 mmol) were combined in a 20 ml sealed tube, and the mixture was heated at 100° C. for 12 h. The mixture was concentrated. To the residue, 10% methanol in DCM (50 ml) was added and the mixture was filtered. The filtrate was concentrated to give a crude product, which was taken in THF/3N HCl (30 ml/15 ml) and the resulting mixture was stirred at 40-45° C. for 12 h. LCMS indicated the completion of reaction with desired product. The mixture was concentrated to give a crude product, which was dissolved in MeOH and H2O (1:1) and purified by preparative HPLC using MeOH/H2O/TFA as solvent system to give (S)-2-amino-3-[4-(2-amino-6-{1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidine-4-yl)-phenyl]-propionic acid as a TFA salt. LCMS: M+1=547. 1H-NMR (400 MHz, CD3OD): δ (ppm) 2.30 (s, 3H), 3.10-3.30 (m, 2H), 4.20 (t, 1H), 6.32 (d, 1H), 6.74 (s, 1H), 7.0 (q, 1H), 7.38 (d, 2H), 7.50 (m, 2H), 7.72 (m, 1H), 7.90 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9](=[O:16])[N:10]([CH2:12][C:13](O)=[O:14])[CH:11]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:47][C:48]([F:60])([F:59])[C:49]1[CH:50]=[C:51]([C:55]([NH2:58])([CH3:57])[CH3:56])[CH:52]=[CH:53][CH:54]=1>CN(C=O)C.O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9](=[O:16])[N:10]([CH2:12][C:13]([NH:58][C:55]([CH3:57])([C:51]3[CH:52]=[CH:53][CH:54]=[C:49]([C:48]([F:59])([F:60])[F:47])[CH:50]=3)[CH3:56])=[O:14])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O
Reactant: CC(C)(N)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)Cn1cc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
45 mg (0.123 mmol) of [4-(5-chloro-2-thienyl)-3-(2-fluorobenzyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-acetic acid from Example 238A, 20 mg (0.147 mmol) of HOBt and 31 mg (0.159 mmol) of EDC hydrochloride are placed in 1.5 ml of DMF and stirred for 10 mins. Next, 30 mg (0.147 mmol) of 1-methyl-1-[(3-trifluoromethyl)phenyl]ethylamine from Example 1A are added and the mixture is stirred overnight at RT. For the workup, the reaction mixture is stirred with 2 ml of water and extracted twice with 5 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 10]. 50 mg (74% of theory) of the target compound are thus obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.C([O-])(=[O:16])C.[Na+].CN(C)C=O>O>[C:8]1([C:5]2[S:6][CH:7]=[C:3]([CH2:2][OH:16])[N:4]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)[O-]
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1csc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 89.9 %

Procedure:
A mixture of 4-chloromethyl-2-phenylthiazole (8.60 g), sodium acetate (10.1 g) and N,N-dimethylformamide (80 ml) was stirred at 80° C. for 6 hours. After cooling, the reaction solution was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. A mixture of the residue, 4N aqueous sodium hydroxide solution (25 ml), tetrahydrofuran (50 ml) and methanol (50 ml) was stirred at room temperature for 5 minutes, and poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-phenyl-4-thiazolylmethanol (7.05 g, yield 90%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from hexane. Melting point: 71–72° C.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4]C.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[Cl:29][C:30]1[CH:37]=[C:36]([C:38]2[NH:39][C:40]3[C:45]([CH:46]=2)=[C:44]([F:47])[CH:43]=[CH:42][CH:41]=3)[C:33]([CH:34]=O)=[CH:32][N:31]=1>C1COCC1.O>[Cl:29][C:30]1[CH:37]=[C:36]([C:38]2[NH:39][C:40]3[C:45]([CH:46]=2)=[C:44]([F:47])[CH:43]=[CH:42][CH:41]=3)[C:33]([CH:34]=[C:3]([CH3:4])[CH3:2])=[CH:32][N:31]=1
Reactant: O=Cc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Reactant: [Li]CCCC
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=Cc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
n-BuLi (3.15 mL, 7.88 mmol, 2.5 M in hexane) was added dropwise to a mixture of isopropyltriphenylphosphonium iodide (3.55 g, 8.21 mmol) in THF (30 mL) at −78° C. under N2 atmosphere. The mixture was stirred at −78° C. for 1 hour. Then a solution of 6-chloro-4-(4-fluoro-1H-indol-2-yl)nicotinaldehyde (900 mg, 3.28 mmol) in THF (10 mL) was added dropwise to the mixture at −78° C. The mixture was stirred at room temperature overnight. The mixture was then diluted with water (100 mL) and extracted with EA (50 mL*3). The organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (PE:EA=4:1) to give the product of 2-(2-chloro-5-(2-methylprop-1-en-1-yl)pyridin-4-yl)-4-fluoro-1H-indole (500 mg, yield: 50.6%). 1H-NMR (CDCl3, 400 MHz) δ 8.66 (br s, 1H), 8.17 (s, 1H), 7.51 (s, 1H), 7.12 (br s, 2H), 6.96 (d, J=1.6 Hz, 1H), 6.70˜6.81 (m, 1H), 6.22 (br s, 1H), 1.97 (s, 3H), 1.68˜1.70 (m, 1H), 1.74 (s, 3H). MS (M+H)+: 301/303.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][C:13]2[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:23])[N:3]=1.[NH:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[N:15]=[C:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])[C:13]([CH2:12][N:4]1[C:5]3=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([C:37]3[CH:38]=[N:34][NH:35][CH:36]=3)=[N:3]1)=[CH:22]2
Reactant: Cc1cccc2cc(Cn3nc(I)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2cc(Cn3nc(-c4cn[nH]c4)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure J using 3-iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.1000 g, 0.178 mmol, 1 eq), pyrazole-4-boronic acid pinacol ester (0.0693 g, 0.357 mmol, 2.0 eq), tetrakis(triphenylphosphine)palladium(0) (0.0206 g, 0.0178 mmol, 10 mol %), and sodium carbonate (2M aq. sol, 0.535 mL, 1.07 mmol, 6 eq) in DMF (1 mL). After purification, 1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained as white solid. The white solid was suspended in CH2Cl2 and filtered to give the desired product as white solid [PI3Kδ IC50=8 nM]. 1H NMR (DMSO-d6) δ ppm 13.17 (1 H, s), 8.22 (1 H, s), 7.97-8.08 (2 H, m), 7.71-7.90 (3 H, m), 7.56-7.66 (3 H, m), 7.52 (1 H, dd, J=7.8, 7.0 Hz), 7.35-7.44 (1H, m), 6.82 (2 H, br. s.), 5.42-5.55 (2 H, m), 2.60 (3 H, s). Mass Spectrum (ESI) m/e=501.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5]([CH2:19][CH2:20][F:21])(C(OCC)=O)[C:6]2=[O:13].[OH-].[Na+].Cl>C1COCC1.CO.O>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:19][CH2:20][F:21])[C:6]2=[O:13]
Reactant: CCOC(=O)C1(CCF)Cc2c(ccc(OC)c2Cl)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1Cl)CC(CCF)C2=O
Reaction time: 3.5 h

Procedure:
To a solution of ethyl 4-chloro-2-(2-fluoroethyl)-5-methoxy-1-oxoindane-2-carboxylate (56.4 g of crude product from the previous reaction) in THF (330 mL) was added methanol (50 mL) followed by a solution of methanol (116 mL)/water (166 mL). To the resulting clear red-orange solution was added SN aqueous NaOH (55.7 mL, 279 mmol) gradually during 9 minutes giving a black solution. After 3.5 hours, the reaction was quenched by addition of 12N aqueous HCl (30 mL, 360 mmol) and most of the THF and methanol were removed by rotary evaporation at reduced pressure. The residue was partitioned between EtOAc and water and the organic phase was washed with saturated aqueous NaHCO3 and brine and dried over MgSO4. Filtration and removal of the solvent under reduced pressure gave crude product. Purification by flash chromatography on silica gel (elution with CH2Cl2) gave the product. Re-purification of mixed fractions gave additional product. The combined yield esd 4-chloro-2-(2-fluoroethyl)-5-methoxyindan-1-one which by NMR contained approximately 4% of the undesired 6-chloro-2-(2-fluoroethyl)-5-methoxyindan-1-one regioisomer.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O.[OH-].[Na+]>CO.O1CCOCC1>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCOCC3)c2n1
Reaction time: 4 h
Yield: 77.7 %

Procedure:
2-Butoxy-8-methoxy-9-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-9H-purin-6-amine (0.11 g) was dissolved in methanol (2 mL) and treated with 4N hydrogen chloride in 1,4-dioxane (1 mL). The reaction mixture was stirred for 4 hours and was stripped to dryness. Water (2 mL) and methanol (15 mL) were added to the residue and then neutralised by the addition of 2N sodium hydroxide solution. The above was stripped to near dryness (small quantity of water remaining) and the solid thus obtained was filtered (transferred and washed the solid with water (3 mL)). The solid was dried under suction before being dried further in vacuo to afford the title compound as a white solid (82 mg).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:5]=2[N:6]=1.[CH2:17]([O:24][C@@H:25]1[C@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:28]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:27][CH:26]1Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CC#N.CCOC(C)=O>[Cl:1][C:2]1[N:3]([C@@H:26]2[O:27][C@H:28]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:29]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:25]2[O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1cc2nc(Cl)[nH]c2cc1[N+](=O)[O-]
Reactant: ClC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1cc2nc(Cl)n([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a mixture of 0.541 g (2.23 mmol) of 2-chloro-5,6-dinitrobenzimidazole in 12 mL of MeCN, was added 0.558 mL (2.23 mmol) of BSA. The reaction mixture was stirred at 75° C. for 15 min to give a clear solution. This solution was treated with the above MeCN solution of 2,3,5-tri-O-benzyl-D-ribofuranosyl chloride and 0.56 mL (2.90 mmol) of TMSOTf at 75° C. for 30 min. The reaction mixture was cooled and diluted with EtOAc (50 mL). The EtOAc solution was washed with sat. NaHCO3 solution (50 mL×2), sat. NaCl solution (50 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (2.2×18 cm, eluted with 20% EtOAc/hexane). Evaporation of fractions 10-14 (20 mL per fraction) gave 0.502 g (35%) of 60 as a syrup. MS: (FAB) m/e 645 (1%, MH+ =645). 1H NMR (DMSO-d6): δ 8.50, 8.49 (2×s, 2, 7-H and 4-H), 7.34, 6.90 (2×m, 15, 3×Ph), 6.09 (d, 1, 1'-H, J1'-2' =8.0 Hz), 4.73~ 4.27 (m, 9, 2'-H, 3'-H, 4'-H, and 3×PhCH2), 3.77 (dd, 1, 5'-H, J4'-5' =2.0 Hz, J5'-5" =11.0 Hz), 3.65 (dd, 1, 5"-H, J4'-5" =2.5 Hz).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH3:4].[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:5]3=[N:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1ccn2c(Br)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cccc(-c2cnc3nc(C)ccn23)c1
Product: N
Temperature: 85 °C
Yield: 177.2 %

Procedure:
A mixture of 3-bromo-7-methylimidazo[1,2-a]pyrimidine (5.3 g, 25 mmol), 3-methoxyphenylboronic acid (4.94 g, 32.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (870 mg, 0.8 mmol) in 1,2-dimethoxyethane (40 ml) was treated with sodium carbonate (18.8 ml of a 2M aqueous solution) then heated at 85° C. for 16 h. The reaction mixture was allowed to cool to ambient temperature then partitioned between ethyl acetate and water. The organics were washed with 10% sodium carbonate solution, water, brine, dried over anhydrous magnesium sulfate, filtered then pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with dichloromethane:conc. ammonia (99.5:0.5) on a gradient of methanol (1-3%) afforded 3-(3-methoxyphenyl)-7-methylimidazo[1,2-a]pyrimidine as a cream-coloured solid (5.3 g, 89%): δH (400 MHz, CDCl3) 2.66 (3H, s), 3.87 (3H, s), 6.76 (1H, d, J 7), 6.95-6.98 (1H, m), 7.03-7.05 (1H, m), 7.09-7.11 (1H, m), 7.44 (1H, t, J 8), 7.80 (1H, s), 8.52 (1H, d, J 7); m/z (ES+) 240 (M++H).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:24]2[CH2:28][CH2:27][CH2:26][CH:25]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C:24]1([C:18]2[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:29])[CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C2=CCCC2)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1C1=CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
The mixture of 2-(2-cyclopent-1-enyl-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (131) (560 mg, 1.43 mmol) and KOH (1 g, 17.9 mmol) is dissolved in EtOH (8 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜3. The precipitate is filtered to give a pure product (132) as a pale yellow solid (518 mg, 100%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([C:16](=[O:26])[CH2:17][CH2:18][CH2:19][C:20]#[C:21][Si](C)(C)C)[N:6]=1)([CH3:4])[CH3:3].O.O.[F-].[K+]>CN(C)C=O>[CH3:4][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[N:8]=[C:7]([C:16](=[O:26])[CH2:17][CH2:18][CH2:19][C:20]#[CH:21])[N:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1nc(C(=O)CCCC#C[Si](C)(C)C)nc(C(C)(C)C)c1O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCCC(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Temperature: 50 °C
Reaction time: 47 h

Procedure:
A mixture of 1-[4,6-bis(1,1-dimethylethyl)-5-hydroxypyrimidin-2-yl]-6-trimethylsilyl-5-hexyn-1-one (0.87 g, 2.3 mmol), Example 8, and potassium fluoride dihydrate (0.91 g, 9.7 mmol) in N,N-dimethylformamide (12 mL) is warmed to 50° C. After stirring for 47 hours at 50° C., the solvent is removed under vacuum and the organic residue is diluted with water. This mixture is extracted with ethyl acetate and the combined extracts are washed with saturated aqueous ammonium chloride solution and brine. The organic is concentrated under vacuum and the organic residue purified by flash chromatorgraphy (SiO2, 20% ethyl acetate (hexane) followed by recrystallization from methanol and water to give 0.48 g (68%) of the title compound), mp 64°-66° C.